Fever

Hesham Waly, MD, FACC

University of Mansoura College of
Medicine
 Introduction
Normal body temperature is maintained,
despite environmental variations,
because the
hypothalamic thermo-regulatory center
balances the excess heat production
(derived from metabolic activity in
muscle and the liver) WITH heat
dissipation from the skin and lungs.
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 The mean oral temperature is 36.8° ± 0.4°C, with
low levels at 6 A.M. and higher levels at 6 P.M.

 Normal diurnal temperature variation is 0.5–1 °C.

 The normal rectal or vaginal temperature is 0.5 °C

> oral temperature, and the axillary temperature is
correspondingly lower.

 Fever: A.M. temperature: >37.2°C OR P.M.

temperature: >37.7°C.
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 FEVER:
Pathophysiology
 Fever: elevation of body temperature > normal
daily variation and occurs in conjunction with
an increase in the hypothalamic set point
i.e. 37°C (normothermic)  39°C (febrile)

 Hyperpyrexia: fever >41.5°C, resulting from

severe infection or CNS hge

 Hypothalamic fever: elevated temperature

caused by abnormal hypothalamic fxn (trauma,
hge, tumor, or intrinsic hypothalamic malfunction).
 Pyrogenic cytokines (IL-1,6, TNF, IFN) and microbial toxins

(Hypothalamic set point (mediated by PGE2 and cAMP (+)

Neurons in vasomotor center (+)

Peripheral VC and increased metabolic activity

(Decrease heat loss peripherally (person feels cold

Shivering“ heat production“

FEVER

 Decreased pyrogens / antipyretic use  reset hypothalamic

set point  VD & sweating (heat loss)
 Pyrogens
 Exogenous pyrogens
– Microbial products
– Microbial toxins
 lipopolysaccahride endotoxin of G-negative bacteria
 Staph aureus enterotoxin
 GAS and GBS
– Whole microorganisms

 Endogenous pyrogens / pyrogenic cytokines

– IL-1, IL-6, TNF, ciliary neurotropic factor (CNTF), IFN-α
– Produced by monocytes, neutrophils, and lymphocytes
– Production can be induced by infection, trauma, inflammation, and
tissue necrosis
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www.MansFans.com
 HYPERTHERMIA
 Hyperthermia is uncontrolled increase in
body temperature > body's ability to lose heat.
In contrast to fever
– The setting of the hypothalamic thermoregulatory center
is unchanged
– Not mediated by cytokines

 Endogenous heat production OR exogenous heat

exposure are two mechanisms by which
hyperthermia can result in dangerously high
internal temperatures.

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 Causes
 Heatstroke
– Exertional: Exercise in higher-than-normal heat and/or humidity
– Nonexertional:
 occurs in very young or elderly, particularly during heat waves.
 Anticholinergics, including antihistamines; antiparkinsonian
drugs; diuretics; phenothiazines

 Malignant Hyperthermia:
– Rare and fatal, DUE TO inherited abnormality of skeletal-
muscle SR that causes rapid increase in intracellular Ca in
response to inhalational anesthetics or succinylcholine.
– Hyperthermia, muscle rigidity, rhabdomyolysis, acidosis, and CV
instability.
 Neuroleptic Malignant Syndrome:
– Rare and fatal, DUE TO idiosyncratic reaction to
major tranquilizers, particularly haloperidol and
fluphenazine.
– Hyperthermia, "lead-pipe" muscle rigidity,
extrapyramidal side effects and autonomic
dysregulation.

 Serotonin Syndrome: Resembles neuroleptic malignant

syndrome BUT
– Occurs within hrs of ingestion of agents that
increase levels of serotonin in the CNS, including
serotonin reuptake inhibitors, MAOIs, TCA
– Distinguished by the presence of diarrhea, tremor,
and myoclonus rather than the "lead-pipe" rigidity
 Drug-Induced Hyperthermia
– Amphetamines, cocaine, phencyclidine (PCP),
methylene-dioxy-meth-amphetamine (MDMA;
"ecstasy"), lysergic acid diethylamide (LSD), salicylates,
lithium, anticholinergics, sympathomimetics

 Endocrinopathy
– Thyrotoxicosis, pheochromocytoma

 CNS Damage
– Cerebral hge, status epilepticus, hypothalamic injury

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 When to suggest hyperthermia
High core temperature in patient with
 Appropriate history (environmental heat
exposure or treatment with anticholinergic
or neuroleptic drugs, TCA, succinylcholine,
or halothane) ALONG WITH
 Appropriate clinical findings (dry skin,
hallucinations, delirium, pupil dilation,
muscle rigidity, and/or elevated levels of
CPK).
Approach to patient with
fever

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 Detailed history
– recent sick contacts
– recent travel (especially overseas deployments or vacations
in the preceding year)
– environmental exposures associated with jobs or hobbies
(such as ticks, mosquitoes, raw sewage, swimming in
ground water, etc.)
– animal exposure (including pets, birds, reptiles)
– unusual dietary habits (such as eating raw seafood,
undercooked meat, or unpasteurized milk)
– high risk behavior (such as IV drug abuse or sexual
behavior--always keep HIV seroconversion in mind)
– detailed history of past surgeries (including prosthetic
material placed)
– hypersensitivities
– family illnesses (CT diseases, malignancies, TB)
Understanding the Fever Pattern

The use of antipyretics can alter fever

pattern, and they are used so often
that "classic" fever patterns are
rarely seen.
For example, the usual times of peak and
trough temperatures may be reversed in
typhoid fever and disseminated TB.
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 Sustained (Continuous) Fever
– Daily elevated temperature (>38 C)
– Fluctuation of elevated temperature < 0.3 C
– Examples: Drug Fever, Salmonella

 Remittent Fever:
– Daily elevated temperature (>38 C)
– Returns to baseline but not to normal

 Intermittent Fever
– Intermittently elevated temperature (>38 C)
– Return to baseline and to normal
 Hectic Fever
– Daily elevated temperature (>38 C)
– Either remittent or intermittent pattern with wide temperature
excursion >1.4 C.
– Examples: Intermittent bacteremia (dental abscess, UTI), EBV , FMF,
Crohn's Disease, Still's Disease (Juvenile RhA).

 Relapsing Fever
– Malaria: Fever every 3rd or 4th day
– Rat Bite Fever: Fever every 3-5 days
– Borrelia species: Fever for days followed by 2-3 wks afebrile
– Brucellosis: Fever for weeks followed by afebrile period that may be
followed by relapse.
– Hodgkin’s Disease (Pel-Ebstein Fever): Fever for 3-10 days
followed by 3-10 days afebrile
– Cyclic Neutropenia: Fever and neutropenia every 3 wks
 Physical examination
 Vital signs: Temperature-pulse dissociation
(relative bradycardia) occurs in typhoid fever,
brucellosis, leptospirosis, some drug-induced
fevers, and factitious fever.

 Skin, eyes, lymph nodes, nail beds, CV system,

chest, abdomen, musculoskeletal system, and
nervous system

 In women: do pelvic exam (possible PID)

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 Laboratory tests
 CBC with special attention paid to the differential.
– Neutrophilia and band forms (as well as toxic granulations and
Dohle bodies): indicate bacterial infection, while Neutropenia: viral
or parvovirus B19, typhoid, brucellosis, TB, histoplasmosis,
infiltrative processes of the BM such as malignancy.

– Lymphocytosis: viral, typhoid, brucellosis, TB, and atypical

lymphocytes: EBV, CMV, HIV, dengue, rubella, measles, varicella,
viral hepatitis

– Monocytosis: typhoid, brucellosis, TB, or lymphoma.

– Eosinophilia: parasitic infections, hypersensitivity drug reaction, or

lymphoma.

 Blood Smear: malarial and babesial pathogens

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 Urinalysis with examination of the urinary sediment is indicated
when symptoms suggest involvement of the GU system.

 Electrolytes, glucose, BUN, and creatinine should be checked as

general measure of the patient’s condition. Liver function tests are
also indicated if signs and symptoms point to hepatic involvement.

 Smears and cultures of specimens from throat, urethra, anus,

cervix, or vagina should be obtained when symptoms or signs
indicate involvement of those systems. Cultures of blood and urine
are indicated whenever the illness is thought to be more than simple
viral infection.

 CSF should be examined and cultured if there is severe headache,

meningismus, change in mental status. If signs of increased ICT
(focal neurologic deficit or papilledema) are present, CT of the head
should be performed to R/O mass lesion before performing lumbar
puncture.
 Any abnormal fluid collection (pleural, peritoneal, or
joint) should be examined and cultured.

 If fever is severe or prolonged → ESR or CRP as

baseline. Non-specific to use for diagnostic purposes, but
can be used to follow the patient’s progress.

 CXR should be considered standard in any patient with

unclear diagnosis or if signs and symptoms point to the
chest. X-rays of other areas, such as the abdomen or an
extremity, may be indicated by the patient’s symptoms.
Repeated Examinations Are
Very Important!

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 TREATMENT OF FEVER

 The objectives in treating fever are:

FIRST to reduce the elevated
hypothalamic set point and SECOND
to facilitate heat loss.
 Oral aspirin and NSAIDs
 In hyperpyrexia: cooling blankets
 TREATING HYPERTHERMIA
 Physical cooling with sponging, fans, cooling
blankets, and even ice baths should be initiated
immediately in conjunction with the
administration of IV fluids

 IV Dantrolene is 1-2.5 mg/kg / 6 hr for 24-48hr,

until PO dantrolene can be administered
Fever of Unknown Origin
 Background
 In 1961, Petersdorf and Beeson defined a
fever of unknown origin (FUO) as the
following:
 Temperature > 38.3°C on several occasions,
 > 3 weeks' duration of illness, and
 Failure to reach a diagnosis despite 1 week
of inpatient investigation.

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 Pathophysiology
 FUOs are caused by:
 Infections (30-40%)
 Neoplasms (20-30%)
 Collagen vascular diseases (10-20%)
 Miscellaneous diseases (15-20%).
 5-15% of FUO cases defy diagnosis,
despite exhaustive studies
 In children, infections are the most frequent cause of
FUOs; While, neoplasms and CT disorders are more
frequent in the elderly.

 In patients with FUOs lasting > 1 year, infections and

neoplasms decline in frequency, and granulomatous
diseases become the most frequent etiology.

 Patients with undiagnosed FUOs (5-15%) generally have

benign long-term course, especially when the fever is not
accompanied by substantial weight loss or other signs of
serious underlying disease.

 In patients > 50 yrs, > 30% of FUO cases are related to CT

disorders and vasculitic disorders. Giant cell arteritis (GCA)
and polymyalgia rheumatica (PMR) are the 2 principal CT
etiologies, and they account for 50% of the cases.
Causes

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 Bacterial diseases
– Consider abscesses, which usually are located intraabdominally,
even in the absence of localizing symptoms.

– TB usually is considered in the FUO differential diagnosis.

– UTIs are rare causes of FUO because urinalysis is an easily

performed routine test.

– Endocarditis. Failure to diagnose it may be due to the absence of

a murmur or the failure of blood cultures to yield the organism.

– Hepatobiliary infections, cholangitis can occur without local

signs and with only mildly elevated or normal liver function tests.

– Osteomyelitis usually causes localized pain or discomfort, at

least intermittently.
 – Brucellosis is very important. Consider this disease in patients with
persistent fever and a history of contact with cattle, swine, goats, and
sheep or in patients who consume raw milk products.

– Systemic infections due to Salmonella species, Neisseria

meningitidis, or Neisseria gonorrhoeae as causes of FUO. Cutaneous
changes may be the only sign other than fever in neisserial infections.
Cultures and serologic tests establish the diagnosis of these infections.

– The most important spirochete is Borrelia recurrentis, which is

transmitted by ticks and is responsible for causing relapsing fever.

 Viral diseases
– HIV: Prolonged febrile episodes are frequent in patients with advanced
HIV infection. 75% of the cases are infectious in nature, about 20-25%
are due to lymphomas, and small fraction (0-5%) is due to HIV itself.

– CMV and EBV can cause prolonged febrile illnesses with constitutional
symptoms and no prominent organ manifestations, particularly in the
elderly.
 Fungi: Immunosuppression, the use of broad-spectrum antibiotics,
the presence of intravascular devices, and TPN all predispose people
to disseminated fungal infections, and Candida albicans is the main
organism.

 Parasites: Consider toxoplasmosis in patients who are febrile with

LN enlargement; Rising antibody titers and IgM antibodies confirm
the diagnosis. If the physician is unaware of history of recent travel to
endemic area and if the fever pattern is nonsynchronized, malaria
can be missed as a cause of fever.

 Rickettsia: Chronic infections with Coxiella burnetii, chronic Q fever,

or Q fever endocarditis are identified in patients with FUO. Signs of
hepatic involvement are frequent, and the infection is transmitted
from cattle and sheep. Perform serologic tests in suspected cases.

 Chlamydia: Consider Chlamydia psittaci, the cause of psittacosis, in

patient with FUO who has history of contact with birds.. Serology is
essential for the diagnosis of chlamydial infections.
 Neoplasms
– Lymphomas: Hodgkin and non-Hodgkin lymphomas frequently cause
fever, night sweats, and weight loss. The diagnosis can be delayed if
the tumor is difficult to detect (eg, when the disease is confined to the
retroperitoneal lymph nodes).

– Leukemias: Acute leukemias are another important neoplastic group

that can cause FUO. In preleukemic states, the peripheral blood smear
and BM aspirate may not reveal the correct diagnosis; therefore, perform
BM biopsy.

– Solid tumors:
 Among solid tumors, renal cell carcinoma most commonly is associated with
FUO, with fever being the only presenting symptom in 10% of cases.
Hematuria may be absent in 40% of cases, whereas anemia and a highly
elevated ESR frequently occur.

 Other solid tumors: Solid tumors such as adenocarcinomas of the breast,

liver, colon, or pancreas and liver metastases from any primary site may
present with fever.
 Collagen vascular and autoimmune diseases: These can present
as FUO if the fever precedes other more specific manifestations (eg,
arthritis, pneumonitis, renal involvement).

– SLE ,nowadays, it is readily diagnosed in most cases by the

demonstration of ANA.

– Systemic-onset JRA is a cause of FUO that often is difficult to

diagnose. High-spiking fevers, non-pruritic rashes, arthralgias and
myalgias, pharyngitis, and lymphadenopathy typically are present.

– Consider other collagen vascular diseases (ie, PAN, RhA, and

mixed CT diseases) because of their potential for nonspecific
presentations. RF can be difficult to diagnose because it is rare in
the developed world .
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– Other vasculitides that cause FUO
 GCA: Classic symptoms include temporal headache, jaw
claudication, fever, visual disturbances ,weight loss, anorexia,
fatigue, and cough.

 PMR: This is characterized by symmetrical pain and stiffness

involving the lumbar spine and large proximal muscles, most
notably the neck, shoulders, hips, and thighs. Symptoms
usually are worse in the morning. Constitutional symptoms (eg,
fever, malaise, depression, weight loss) also are observed.

 PAN: ranks a distant third as a cause of FUO.

 Granulomatous diseases
– Sarcoidosis: Given its multiorgan involvement, it rarely manifests with
fever and malaise without evidence of LN and pulmonary involvement.
Erythema nodosum occasionally is present, and the finding of
noncaseous granulomas in the liver should raise concern.

– Regional enteritis: Crohn disease is the most common GI cause of

FUO. Diarrhea and other abdominal complaints are common. Diagnose
by endoscopy and biopsy.

– Hepatic granuloma: TB, syphilis, brucellosis, sarcoidosis, Crohn

disease, Hodgkin disease.

 Endocrine
– Hyperthyroidism
– Adrenal insufficiency. Consider it in patients with nausea, vomiting,
weight loss, skin hyperpigmentation, hypotension, hyponatremia, and
hyperkalemia.
 Miscellaneous causes
– Peripheral PE and occult thrombophlebitis can cause FUO.

– Factitious fever is responsible for as many as 10% of FUO cases.

Rapid changes of body temperature without associated shivering or
sweating, large differences between rectal and oral temperature, and
discrepancies between fever, pulse rate, or general appearance typically
are observed in patients who manipulate or exchange their
thermometers, the most common cause of factitious fever.

– Drug fever: The most common are beta-lactam antibiotics,

procainamide, isoniazid, alpha-methyldopa, quinidine, and
diphenylhydantoin. When suspecting drug fever, discontinue the
implicated drug. If the drug, in fact, was responsible for the fever,
stopping the drug generally leads to defervescence within 2 days.

– Inherited diseases: FMF most often is found, but not exclusively, in

patients of Mediterranean descent. Recurrent febrile episodes at varying
intervals are associated with pleural, abdominal, or joint pain due to
polyserositis. This is a diagnosis of exclusion.
Clinical

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 History
 Diagnostic approach to adults with FUO
– Inquire about symptoms from all major organ systems, including a
detailed history of general complaints (eg, fever, weight loss, night
sweats, headaches, rashes).

– Record all complaints, even if they disappeared before the exam.

Previous illnesses are important, including surgeries and psychiatric
illnesses.

– Provide a detailed evaluation including the following:

 Family history
 Immunization status
 Occupational history
 Travel history
 Nutrition (including consumption of dairy products)
 Drug history (over-the-counter medications, prescription
medications, illicit substances)
 Sexual history
 Recreational habits
 Animal contacts (including exposure to ticks and other vectors)
 Physical
 Definitive documentation of fever and exclusion of factitious fever are
essential early steps in the physical exam.
– Measure the fever more than once.
– Electronic thermometers facilitate the rapid and unequivocal
documentation of fever.

 The pattern of fever (continuous, remittent, intermittent) usually is of

little help in the evaluation.
– In general, correlation between fever patterns and specific diseases
is weak. Notable exception is malaria.
– Other diseases (eg, brucellosis, borreliosis, Hodgkin disease) tend
to cause recurrent episodes of fever.

 Repeat physical exam daily while the patient is hospitalized. Pay

special attention to rashes, new or changing cardiac murmurs, signs of
arthritis, abdominal tenderness or rigidity, LN enlargement,
funduscopic changes, and neurologic deficits.
Work up
 Lab Studies:
– CBC count and microscopic examination
– Anemia suggests serious underlying disease.
– NOT miss leukemias in aleukemic or preleukemic cases.
– Lymphocytosis with atypical cells suggests herpesvirus.
– Leukocytosis suggests occult bacterial infection.
– Direct exam of peripheral blood smear to diagnose malaria and
spirochetal diseases.

– Urinalysis:
– Exclude UTIs and malignant tumors of the urinary tract; however, not
all of them consistently are associated with pathologic findings in the
urine.

– Serum chemistry
– At least one liver function test is usually abnormal, with an underlying
disease originating in the liver or a disease that causes nonspecific
alterations of the liver (eg, granulomatous hepatitis).
 Cultures
– Blood cultures are essential in the evaluation.
– Routinely culture the patients' urine.
– Cultures of sputum and stool may be helpful in the presence of signs
or symptoms suggestive of pulmonary or GI disease, respectively.
– Obtain cultures of tissues and liquids that are sampled during
workup. These tissues and fluids include CSF, pleural or peritoneal
fluid, and fluid from the liver, bone marrow, and lymph nodes.

 Serologies
– Serologies are most helpful if paired samples show significant,
usually 4-fold, increase of antibodies specific to infectious
microorganism.

 Other tests
– Frequently check ANA titers, rheumatologic factor, thyroxine level,
and ESR because they are helpful in diagnosing selected condition
(SLE, RhA, thyroiditis, hyperthyroidism, GCA, PMR).
 Imaging Studies:
– Routinely CXR.

– Routine abdominal US, even in the absence of signs of an

intraabdominal process.

– CT scans
 If US studies fail to help reveal the diagnosis, obtain CT scans of the
abdomen in all patients with
– symptoms suggesting intraabdominal process,
– suspected retroperitoneal tumors or infections,
– abnormal liver function tests.

 IV pyelography may be more sensitive than the CT scan in detecting

processes involving the descending urinary tract, but the CT scan is
preferred for most other processes of the retroperitoneal space.

– MRI can be very useful in cases where osteomyelitis is suspected.

 Other Tests:
– Endoscopic examination
 Endoscopic exam of the upper and lower GI tract, including
retrograde cholangiography when searching for Crohn disease,
Whipple disease, biliary tract disease, and GI tumors.
 Occasionally, complementing endoscopic studies with barium
enemas or upper GI series is necessary.

– Radionucleotide studies
 V/Q scan to document PE. Obtain pulmonary angiography when
suspecting PE.
 Tc bone scan for diagnosis osteomyelitis.
 Gallium citrate or granulocytes labeled with indium In 111 scan for
diagnosis of occult abscesses.

– ECHO: This technique is highly sensitive in diagnosing endocarditis.

 The final diagnosis is obtained during direct
biopsy examination of involved tissue.

– Biopsies are easily performed in enlarged accessible lymph

nodes, other peripheral tissues, and bone marrow.

– The decision to biopsy is more difficult if it necessitates

exploratory surgical procedure (eg, laparotomy). This rarely
is indicated (eg, when imaging techniques are nondiagnostic
and an intraabdominal source is suspected).

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Treatment

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 Medical Care: Direct treatment toward the underlying cause.

 Surgical Care: Because of a better understanding of the

etiologies and careful diagnostic approaches, patients with FUO
rarely need surgical treatment.

 Further Inpatient Care:

– 5-15% of patients remain undiagnosed, even after extensive
evaluations. These patients usually have benign long-term
course, especially in the absence of substantial weight loss
or other signs of serious underlying disease.

– No evidence supports prolonged hospitalization in patients

who are clinically stable and whose workup is unrevealing.
THANK YOU

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